There is evidence that the complement system, a major component of inflammatory responses, may play an important role in neurodegenerative conditions such as Alzheimer's disease (AD). The proposed studies focus on elucidating the role of the anaphylatoxin CSa in mechanisms of neurodegeneration. During the past grant period, the investigators have demonstrated that mice genetically deficient in the complement component CS are more susceptible to excitotoxic neurodegeneration, and that the C5-derived anaphylatoxin C5a may protect against glutamate and p-amyloid (Ap) mediated neurotoxicity in part through inhibition of caspase 3, an executioner of apoptotic dell death. This neuroprotective role of CSa complicates current theories that complement proteins may be involved in the pathogenesis of AD neurodegeneration. For the next grant period, they propose to extend this novel finding with a focus on CSa mediated signal transduction mechanisms involved in neuroprotection. Ongoing studies suggest that human recombinant (hr) CSa may neuroprotect against glutamate and Abeta 1-42 mediated neurotoxicity through mechanisms that involve inhibition of caspase and activation of mitogen activated protein (MAP)- kinase pathways. Further characterization of the complex role of complement proteins in neurodegeneration is essential especially in view of the possibility that the complement system represents a target for therapeutic interventions in AD.